Iron is an essential trace element required for growth and development of all living organisms. Iron content in mammals is regulated by controlling iron absorption, iron recycling, and release of iron from the cells in which it is stored. Iron release is controlled by ferroportin, a major iron export protein located on the cell surface of enterocytes, macrophages and hepatocytes, the main cells capable of releasing iron into plasma. Ferroportin, also known as MTP1 or Ferroportin-1, is a multipass transmembrane protein that mediates cellular iron efflux (Donovan et al., Nature, 403:776-781, 2000; Abboud et al., J. Biol. Chem., 275:19906-19912, 2000). Ferroportin is highly expressed in duodenal enterocytes and macrophages of the reticuloendothelial system where it is involved in transport of iron from the diet and the recycling of iron from senescent red blood cells, respectively (Yang et al., J. Biol. Chem., 277:39786-39791, 2002). Ferroportin is negatively regulated by the iron-regulatory hormone hepcidin. Hepcidin has been shown to bind ferroportin, resulting in internalization and degradation of ferroportin (Nemeth et al., Blood, 107:328-333, 2006; Nemeth et al., Science, 306:2090-2093, 2004; de Domenico et al., Mol. Biol. Cell., 8:2569-2578, 2007). This mechanism blocks the release of iron from macrophages, hepatocytes and enterocytes (Knutson et al., Proc. Natl. Acad. Sci. USA, 102:1324-1328, 2008; Nemeth et al., Blood, 107:328-333, 2006; Knutson et al., Blood, 102:4191-4197, 2003).
Ferroportin is important for iron efflux as demonstrated in transgenic mice: deletion of ferroportin is embryonically lethal whereas inactivation of ferroportin by a conditional knockout results in increased iron storage in enterocytes, macrophages and hepatocytes (Donovan et al., Cell. Metab., 1:191-200, 2005). Thomas and Oates, Gut, 2004; 53; 44-49, reported that a polyclonal antibody generated using a rat ferroportin peptide sequence Genbank Accession No. AAK77858 (predicted to be between transmembrane domains 3 and 4) reduced cellular iron uptake but had no effect on iron release.